As a blood purification therapy using a hollow fiber membrane, medical treatment of chronic renal failure by hemodialysis, an apheresis treatment, and the like are widely performed. Especially, in the field of hemodialysis treatment, the number of hemodialysis patients has considerably increased with the progress in the method of treatment. For example, the number of dialysis patients in Japan has already exceeded 200,000 and the number of hemodialysis patients on a long-term basis is also increasing. In these circumstances, various dialysis complications, such as disorders caused by accumulation of uremic substances in specific sites or organs following a long dialysis period, metabolic disorders resulting from improper removal of specific uremic substances, and the like, are acknowledged as problems. A medical treatment for improving the quality of life (QOL) of the dialysis patients by positively removing uremic substances leading to a dialysis complication is being tested.
On the basis of these purpose, a number of studies on hollow fiber membranes for blood purification are ongoing with the objective of improving permeability of specific substances through the membrane by reviewing the structure, composition, and properties of hollow fiber membranes. Specific examples of such studies include a study for increasing pore size of the membrane for removing uremic proteins (also referred to as “low-molecular-weight proteins”), a study for improving fractionability of the membrane for permeating low-molecular-weight proteins with a molecular weight smaller than biologically useful albumin, while inhibiting permeation or loss of such useful substances, and a study for improving membrane surface properties of selectively permeating not only such low-molecular-weight proteins, but also charged low-molecular-weight nonprotein uremic substances.
Of the complications actualized by a long-term dialysis treatment, dialysis amyloidosis is a well known typical example of the complication which is caused by uremic low-molecular-weight proteins. In an effort to combat the dialysis amyloidosis, various studies have been undertaken to increase sharpness of fractionability of hollow fiber membranes by improving the membrane's capability of removing β2-Microglobulin, which is a substance causing the dialysis amyloidosis, while inhibiting permeation of biologically useful albumin. In addition, with an objective of more efficiently ameliorating the dialysis amyloidosis, a study for removing α1-microglobulin, which is a uremic low-molecular-weight protein similar to β2-microglobulin, is ongoing.
For example, Patent document 2 discloses a membrane with an improved permeation balance and a high water permeability, while inhibiting leakage of proteins, by localizing hydrophilic polymer in a dense layer near the inner surface of the membrane. However, this membrane is not satisfactory due to permissive requirement for albumin permeation as evidenced by the description in paragraph [0062] of the document 2 stating that “non-permeability of albumin is defined as having an albumin permeation rate of 5% or less”. The description only mentions that the amount of leaked albumin is small in relation to water permeability, which is a technique simply achievable by a small pore diameter, and the document does not describe or suggest the capability of fractionating into different low-molecular-weight proteins. Thus, usefulness of the invention for improving the complication caused by long-term dialysis is not clear.
As prior art documents concretely disclosing capability of fractionating into low-molecular-weight proteins and albumin, Patent documents 3 and 4 can be given. Patent document 3 discloses a method for increasing selective separation performance of a membrane by enabling multi-layer filtration by increasing the thickness of a dense layer which functions as a selective separation layer by controlling membrane-forming conditions. According to this method, it is possible to inhibit albumin leakage in spite of the use of a membrane with a large pore diameter which permits sufficient removal of low-molecular-weight proteins. Patent document 4 discloses a blood purification membrane in which the permeation rate of polyvinylpyrrolidone with a molecular weight of 40,000 and the permeation rate of albumin are specified. The permeation rate of polyvinylpyrrolidone here is used as an index corresponding to the permeation rate of β2-Microglobulin, which is a low-molecular-weight protein. The patent document 4 discloses a hollow fiber membrane that can remove the β2-microglobulin while inhibiting permeation of albumin.
On the other hand, complications that are induced by not only accumulation of the low-molecular-weight proteins but also accumulation of uremic substances with a far smaller molecular weight than the low-molecular-weight proteins are known among the complications caused by long-term dialysis treatment. As a typical example, bone metabolism disorders induced by a high in vivo concentration of phosphate ion which is a charged inorganic substance can be given. In order to promote performance of membranes for removing phosphorus compounds which are causative substances, various studies on improvement mainly of surface properties of hollow fiber membranes are ongoing. Charges on the inner surface of a hollow fiber membrane coming in contact with blood are thought to be an important factor which determines the phosphorus-removing performance. A zeta potential is one of the indices expressing charges. It is known that the phosphorus-removing performance decreases when the zeta potential is negative and increases when the zeta potential is positive (Non-patent document 1). There is a report stating that, in general, when the zeta potential on the membrane surface is charged with positive charges of 0 mV or more, blood cells such as platelets, of which the cell membrane surface is negatively charged, are easily adsorbed on the membrane surface. Particularly, if platelets adhere and are activated, a blood coagulation system is activated and phenomena such as worsening of blood-remaining properties and the like easily occur, with a consequence of inferior antithrombogenicity.
Contrary, if a hollow fiber membrane having strong negative charges is used in a hemodialysis treatment, not only phosphorus-removing performance decreases due to electric repelling, but also the bradykinin value increases, giving rise to an anaphylactoid reaction. Since the bradykinin value further increases by the use of an ACE inhibitor, the use of a membrane strongly charged with negative charges requires stringent care. For this reason, in order to increase phosphorus-removing performance without impairing antithrombogenicity of a membrane, and yet inhibiting anaphylaxis, a membrane with a strictly controlled negative charge distribution and size of the charges was thought to be required.
Patent document 1, for example, describes a composite hollow fiber membrane which has negative charges on the inner surface and more positive charges toward the outer from the inner surface. However, the membrane does not exhibit sufficient phosphorus-removing performance because of a possible reason that the effect resulting from controlling appropriate negative charges on the inner surface has not been discovered. Specifically, although the document 1 describes the data that phosphorus clearance of a module with a membrane area of 1.0 m2 is 132 ml/min, a phosphorus clearance rate for a membrane area of 1.5 m2 equivalent calculated based on the overall mass transfer coefficient of phosphorus obtained from this value is found to be only as small as 156 ml/min. In addition, although the membrane disclosed in Patent document 4 is a polymer blend membrane containing a hydrophobic polymer and a hydrophilic polymer, it did not consider the charges on the inner surface. Non-patent document 1 describes a general concept of the zeta potential on the membrane surface and the phosphorus-removing performance as mentioned above, but the document does not present any direct suggestions on a system with more complicated membrane surface properties such a polymer blend membrane comprising a hydrophobic polymer and a hydrophilic polymer as disclosed in the present invention.
As described above, although various studies have been undertaken on the improvement of hollow fiber membranes for blood purification with an objective of ameliorating the complications caused by long-term dialysis, none of the efforts heretofore have been successful in obtaining a hollow fiber membrane that can satisfy the requirements for ameliorating each of the complications. In addition, the past studies focus their target exclusively on removal of the substance causing the individual complication in question and, therefore, have not found a hollow fiber membrane which is more effective for ameliorating complications by, for example, sufficiently removing charged inorganic substances while also sufficiently removing low-molecular-weight proteins.
[Patent document 1] Japanese Patent Application Laid-open No. 04-7024
[Patent document 2] Japanese Patent Application Laid-open No. 04-300636
[Patent document 3] Japanese Patent Application Laid-open No. 10-243999
[Patent document 4] Japanese Patent Application Laid-open No. 2003-33432
[Non-patent document 1] “The high performance membrane for hemodialysis stuff”, Tokyo Igakusha Co., Ltd., pages 130-131 (1990)